Alagille's syndrome
Prof. J. Reichen

First described by Alagille in 1969, reported in the English literature in 1975 (1). Synonyms: arteriohepatic dysplasia, syndromatic ductopenia.

Genetics:
Autosomal dominant disorder owing to mutations in the JAG1 gene on chromosome 20p12 (2;3). JAG1 codes for a NOTCH receptor ligand important in cell-cell interactions and in development. Different mutations have been described 70 % of which are sporadic (4). During embroygenesis JAG1 is expressed mainly in the cardiovascular system; in the liver it is associated with blood vessels. It is also expressed in other structures of mesenchymal origin suggesting that the variety of associated conditions are not chance associations (5). In mice, JAG1 expression is modified by Fringe, why may account for the variable phenotypes in individuals with the same genotype (26). Furthermore, NOTCH mutations on chromosome 1p13-p11 can lead to a phenotype similar to the original description with less cardiac and renal involvement. Consequently, OMIM describes two forms:
AGS1 - corresponding to the syndrome initially described by Alagille and
AGS2 - related to mutations in the NOTCH gene. In contrast to AGS1 there is less cardiac and renal involvement.

Clinical presentation, associated features:
The classical syndrome consists of jaundice in early infancy, characteristic facies, pulmonary stenosis, butterfly vertebrae, growth and mental retardation and hypogonadism (1). In Emerick's series, 40 % had renal disease and stroke occurred in 14 % (6). The growth retardation is due to resistance to GH (7). Severe pruritus occurs in 45 % but can abate with age (6). Besides posterior embryotoxon a variety of other ocular anomalities have been described (8).

Other associated conditions include congenital mechanical obstruction of the small intestine (10), cystic renal disease (11), tubulo-interstitial nephropathy (12), exocrine pancreatic insufficiency (13), pancreas atrophy with diabetes mellitus (14), coproporphyrin abnormalities with photosensitivity (15).

Natural history:
The 20 year life expectancy is 75 %, factors contributing to mortality are complex congenital heart disease (15 %), intracranial bleeding (25 %) and hepatic disease potentially leading to hepatic transplantation (6). In smaller series, the likelihood to reach adulthood without transplantation was only 50 % (16;17). Hepatocellular cancer is rare but has been described in a non-cirrhotic liver at age 36 (18). In one family 3/4 sibs succumbed to liver cancer in childhood (19). In a case with recurrence 13 years after successful resection there was marked dysplasia in noncirrhotic liver (20).

Liver biopsy:
The typical feature is paucity of bile ducts; this can be difficult to recognize in biopsies obtained in infancy (21). Paucity can be progressive with time (6).

Treatment:
Substitution of fat soluble vitamins, medium chain triglycerides for failure to thrive (22) and the usual treatment of pruritus (23). External biliary diversion can provide relief from refractory pruritus (24). OLT should be considered for severe forms, in particular intractable pruritus or severe growth retardation (25).

References

1. Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr 1975; 86(1):63-71.
2. Oda T, Elkahwaji J, Pike BL, et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nature Genet 1997; 16:235-242.
3. Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1 which encodes a ligand for Notch1. Nat Genet 1997; 16:243-251.
4. Crosnier C, Driancourt C, Raynaud N, Dhorne-Pollet S, Pollet N, Bernard O et al. Mutations in JAGGED1 gene are predominantly sporadic in alagille syndrome. Gastroenterology 1999; 116(5):1141-1148.
5. Crosnier C, Attié-Bitach T, Encha-Razavi F, Audollent S, Soudy F, Hadchouel M et al. JAGGED1 gene expression during human embryogenesis elucidates the wide phenotypic spectrum of Alagille syndrome. Hepatology 2000; 32(3):574-581.
6. Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92 patients: Frequency and relation to prognosis. Hepatology 1999; 29(3):822-829.
7. Bucuvalas JC, Horn J, Carlsson L, Balistreri W, Chernausek S. Growth hormone insensitivity associated with elevated circulating growth hormone-binding protein in children with alagille syndrome and short stature. J Clin Endocrinol Metab 1993; 76:1477-1482.
8. Hingorani M, Nischal KK, Davies A, Bentley C, Vivian A, Baker AJ et al. Ocular abnormalities in Alagille syndrome. Ophthalmology 1999; 106(2):330-337.
9. Alagille D, Estrada A, Hadchouel M, Gautier M, Odievre M, Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): Review of 80 cases. J Pediatr 1987; 110:195-200.
10. Chiu HH, Chang MH, Chen CL, Hsu HY, Ni YH. The association of syndromatic paucity of the interlobular bile ducts and congenital mechanical obstruction of the small intestine. J Ped Gastroent Nutr 1995; 21(3):304-307.
11. Martin SR, Garel L, Alvarez F. Alagille's syndrome associated with cystic renal disease. Arch Dis Child 1996; 74:232-235.
12. Hyams JS, Berman MM, Davis BH. Tubulointerstitial nephropathy associated with arteriohepatic dysplasia. Gastroenterology 1983; 85:430-434.
13. Chong SKF, Lindridge J, Moniz C, Mowat AP. Exocrine pancreatic insufficiency in syndromic paucity of interlobular bile ducts. J Ped Gastroent Nutr 1989; 9:445-449.
14. Devriendt K, Dooms L, Proesmans W, De Zegher F, Desmet V, Eggermont E. Paucity of intrahepatic bile ducts, solitary kidney and atrophic pancreas with diabetes mellitus: Atypical Alagille syndrome. Eur J Pediatr 1996; 155:87-90.
15. Poh-Fitzpatrick MB, Zaider E, Sciales C, Sokol RJ , Tobin CE, Knobler E et al. Cutaneous photosensitivity and coproporphyrin abnormalities in the Alagille syndrome. Gastroenterology 1990; 99:831-835.
16. Hoffenberg EJ, Narkewicz MR, Sondheimer JM, Smith DJ, Silverman A, Sokol RJ. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr 1995; 127:220-224.
17. Quiros-Tejeira RE, Ament ME, Heyman MB, Martin MG , Rosenthal P, Hall TR et al. Variable morbidity in alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr 1999; 29 (4):431-437.
18. Adams PC. Hepatocellular carcinoma associated with arteriohepatic dysplasia. Dig Dis Sci 1986; 31:438-442.
19. Rabinovitz M, Imperial JC, Schade RR, Van Thiel DH. Hepatocellular carcinoma in Alagille's syndrome: A family study. J Ped Gastroent Nutr 1989; 8:26-30.
20. Le Bail B, Bioulac-Sage P, Arnoux R, Perissat J, Saric J, Balabaud C. Late recurrence of a hepatocellular carcinoma in a patient with incomplete Alagille syndrome. Gastroenterology 1990; 99:1514-1516.
21. Dahms BB, Petrelli M, Wyllie R, Henoch MS, Halpin TC, Morrison S et al. Arteriohepatic dysplasia in infancy and childhood: A longitudinal study of six patients. Hepatology 1982; 2:350-358.
22. Alagille D. Management of paucity of interlobular bile ducts. J Hepatol 1985; 1:561-565.
23. Reichen J. Pharmacologic treatment of cholestasis. Semin Liver Dis 1993; 13:302-315.
24. Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology 1988; 95:130-136.
25. Cardona J, Houssin D, Gauthier F, Devictor D, Losay J, Hadchouel M et al. Liver transplantation in children with Alagille syndrome - A study of twelve cases. Transplantation 1995; 60:339-342.
26. Ryan MJ, Bales C, Nelson A et al. Bile duct proliferation in Jag1/Fringe heterozygous mice identifies candidate modifiers of the Alagillle syndrome hepatic phenotype. Hepatology 2008; 48: 1989-1997.

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